Human cytomegalovirus (HCMV) is a herpesvirus that causes widespread infection found across all geographic locations and socio-economic groups, with up to 85% of adults infected by age 40 in the United States. For most healthy people who acquire the virus after birth there are no long-term consequences. However, the risk of HCMV infection is significant for several high-risk groups including: (i) unborn children, (ii) adults who work with children, and (iii) immuno-compromised persons. The prevalence of these risk groups underlies the importance of the development of a safe and efficacious vaccine.
HCMV is typically secreted via a number of bodily fluids, e.g., saliva, urine and semen. Thus, transmission of the virus between people can occur through either sexual or non-sexual contact. An individual can contract HCMV through blood or organ transplants, and a mother can transmit it to her unborn fetus.
The virus demonstrates a life-long latency, but is most commonly non-symptomatic in healthy individuals. It sometimes can cause an illness with symptoms similar to those associated with mononucleosis. However, it can cause severe illness in immunocompromised individuals, e.g., transplant recipients or those with acquired immunodeficiency syndrome (AIDS), in addition to the severe, debilitating effects on unborn children whose immune systems have not yet matured.
In the case of transplants, bone marrow transplant recipients show a relatively high incidence of HCMV-induced pneumonia, with consequent high mortality among these patients. In solid organ transplant patients, disease triggered by HCMV can include a HCMV syndrome (consisting of fever and leucopenia), hepatitis, colitis and pneumonia. HCMV-induced disease in these transplant recipients is caused by the immunosuppressive effects of the drugs required for transplant acceptance and the induction of graft vs. host disease (GVHD). The GVHD effect is most severe in those instances where the organ/marrow donor is HCMV seropositive and the recipient is HCMV seronegative.
For AIDS patients, HCMV is the most common opportunistic infection, in large part due to the fact that greater than 90% of HIV-infected individuals are co-infected with HCMV. In these patients, the infection most commonly manifests as retinitis, and usually occurs when the CD4+ cell counts are less than 50/μl. Prior to the adoption of highly active antiretroviral (HAART) protocols, 20-44% of AIDS patients developed HCMV disease. While the use of HAART has also resulted in the reduction of HCMV disease, the unavailability of HAART for many AIDS patients, as well as the inability of many patients to tolerate HAART for extended periods of time, make the possibility of HCMV disease a continuing concern.
Congenital HCMV, a result of mother-to-fetus transmission, occurs at an overall rate of approximately 1%, but rates are much higher and symptomatic disease is more common when the mother has a primary infection. Women can be infected via sexual contact, since shedding of the virus from the cervix and in semen is common. Infected infants can remain viremic for up to five years after birth, becoming an important source for infection in day care settings.
Congenital HCMV can have horrific manifestations in infants. A fulminant cytomegalic inclusion disease can develop, characterized by jaundice, petechial rash, hepatosplenomegaly, microcephaly, and chorioretinitis. There is often progressive hearing loss and mental retardation, which can be severe. The estimated costs to society in terms of care for victims of congenital HCMV are approximately four billion dollars.
Thus, there remains a clear need for a safe and effective vaccine to combat HCMV infection, both prophylactically (for example, in adolescents or women of child-bearing potential to prevent congenital infection or in HCMV-uninfected transplant candidates) and therapeutically (for example, in HCMV-infected transplant patients prior to and after transplantation of an organ or bone marrow).